G3139, an anti-Bcl-2 antisense oligomer that binds heparin-binding growth factors and collagen I, alters in vitro endothelial cell growth and tubular morphogenesis.
G3139, an anti-Bcl-2 antisense oligomer that binds heparin-binding growth factors and collagen I, alters in vitro endothelial cell growth and tubular morphogenesis.
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DOI：
10.1158/1078-0432.ccr-08-2610
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Benimetskaya L
中科院分区：
文献类型：
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作者：
Stein CA;Wu S;Voskresenskiy AM;Zhou JF;Shin J;Miller P;Souleimanian N;Benimetskaya L
我们研究了G3139对肝素结合蛋白（如FGF2和I型胶原）与内皮细胞相互作用的影响。G3139是一种靶向Bcl-2 mRNA起始密码子区域的18聚硫代寡核苷酸。一项针对晚期黑色素瘤（GM301）的随机、前瞻性全球III期试验评估了G3139联合达卡巴嗪的疗效。然而，G3139的作用机制尚不完全清楚，因为Bcl-2沉默不太可能是黑色素瘤细胞化学致敏的唯一机制。测定了G3139与肝素结合蛋白相互作用和保护的能力。在HMEC-1和HUVEC细胞中，测定G3139对FGF2与高亲和力细胞表面受体结合、诱导细胞有丝分裂和小管形态发生的影响。通过替代肝素，G3139可以增强FGF2与FGFR1 IIIc的结合，并保护FGF免受氧化和蛋白水解。G3139可以促进3D胶原凝胶中内皮细胞的有丝分裂和HMEC-1细胞的管状形态发生，同样可以促进HUVEC细胞的有丝分裂，并在大鼠主动脉环模型中诱导血管发芽。G3139显著影响内皮细胞的行为。这一观察结果可能与临床观察到的LDH治疗相互作用有关。
We examined the effects of G3139 on the interaction of heparin-binding proteins (e.g., FGF2 and collagen I) with endothelial cells. G3139 is an 18mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. A randomized, prospective global Phase III trial in advanced melanoma (GM301) has evaluted G3139 in combination with dacarbazine. However, the mechanism of action of G3139 is incompletely understood, as it is unlikely that Bcl-2 silencing is the sole mechanism for chemo-sensitization in melanoma cells. The ability of G3139 to interact with and protect heparin-binding proteins was quantitated. The effects of G3139 on the binding of FGF2 to high affinity cell surface receptors, and the induction of cellular mitogenesis and tubular morphogenesis in HMEC-1 and HUVEC cells were determined. G3139 binds with picomolar affinity to collagen I. By replacing heparin, the drug can potentiate the binding of FGF2 to FGFR1 IIIc, and it protects FGF from oxidation and from proteolysis. G3139 can increase endothelial cell mitogenesis and tubular morphogenesis of HMEC-1 cells in 3D collagen gels, increases the mitogenesis of HUVEC cells similarly, and induces vessel sprouts in the rat aortic ring model. G3139 dramatically affects the behavior of endothelial cells. There may be a correlation between this observation and the treatment interaction with LDH observed clinically.